In this P50 renewal application, we propose to build upon our progress to identify promising new smoking cessation treatments adapted to individual smokers according to their baseline characteristics and initial response to treatment. In the previous period of support, we showed that the initial response to nicotine patch treatment in the week before a target quit-smoking date predicted long-term abstinence. Using this early marker of therapeutic response, we demonstrated that switching patch non-responders to alternative treatments rescued a significant proportion of would-be treatment failures. In addition, our Center's Preclinical Studies screened and identified several promising new treatments, including lorcaserin (a 5-HT2C agonist that is FDA-approved for weight loss) and amitifadine (a triple serotonin-norepinephrine-dopamine reuptake blocker having anti-depressant effects), which will be carried forward into clinical studies in the proposed work. The proposed continuation of our Center includes three research projects: 1) Clinical Trials, which will evaluate the efficacy of three novel approaches targeting the following distinct populations: 1) women concerned about weight gain after quitting smoking, who have are especially prone to relapse. We will evaluate the efficacy of lorcaserin in this population; 2) smokers for whom the inhalational aspects of smoking are important, a need that is not well addressed by conventional nicotine replacement therapy (NRT). Electronic nicotine delivery systems (ENDS), which provide replacement of both nicotine and key inhalational aspects of smoking behavior, will be evaluated in these smokers; and 3) smokers concerned about negative mood consequences of quitting smoking, which confers greater risk of relapse. In these smokers, we will evaluate the efficacy of the tripl reuptake blocker, amitifadine. In each study, participants will be assessed after the first week of treatment using a battery of measures, to identify and validate early markers of treatment outcome; 2) Translational Clinic, which will implement the adaptive treatment algorithm developed under the previous P50 support in a real-world setting, where treatment is provided to a more diverse population of smokers than is typically studied in randomized controlled trials; abstinence outcomes and cost effectiveness will be assessed; 3) Preclinical Studies, which will continue to screen promising drugs and drug combinations for their effects in blocking nicotine self-administration behavior, and to identify brain mechanisms underlying the therapeutic effects of different pharmacologic agents. These three projects will be supported by an Administrative Core, which will not only oversee and coordinate the research projects, but will also orchestrate training and education of students and post-doctoral fellows, and disseminate findings to treatment providers, public policy makers and the lay public. In this manner, the Center can serve as national resource to promote improved smoking cessation treatment throughout the nation's health care system. The dissemination of this knowledge will help reduce, and ultimately end, the enormous burden of death and disease caused by cigarette smoking.